The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib

Karthick Vishwanathan*, Paul A. Dickinson, Karen So, Karen Thomas, Yuh-Min Chen, Javier Carpeno, Anne-Marie C. Dingemans, Hye Ryun Kim, Joo-Hang Kim, Matthew G. Krebs, James Chih-Hsin Yang, Bui Bui, Doris Weilert, R. Donald Harvey

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

AimsWe investigated the effects of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampicin) on the pharmacokinetics of the epidermal growth factor receptor-tyrosine kinase inhibitor osimertinib, in patients with advanced non-small cell lung cancer in two Phase I, open-label, two-part clinical studies. Part one of both studies is reported. MethodsIn the itraconazole study (NCT02157883), patients received single-dose osimertinib 80mg on Days 1 and 10 and itraconazole (200mg twice daily) on Days 6-18 orally. In the rifampicin study (NCT02197247), patients received osimertinib 80mg once daily on Days 1-77 and rifampicin 600mg once daily on Days 29-49. ResultsIn the itraconazole study (n=36), the geometric least squares mean (GMLSM) ratios (osimertinib plus itraconazole/osimertinib alone) for C-max and AUC were 80% (90% CI 73, 87) and 124% (90% CI 115, 135), respectively, below the predefined no-effect upper limit of 200%. In the rifampicin study (n=40), the GMLSM ratios (osimertinib plus rifampicin/osimertinib alone) for C-ss,C-max and AUC were 27% (90% CI 24, 30) and 22% (90% CI 20, 24), respectively, below the predefined no-effect lower limit of 50%. The induction effect of rifampicin was apparent within 7 days of initiation; osimertinib C-ss,C-max and AUC values returned to pre-rifampicin levels within 3 weeks of rifampicin discontinuation. No new osimertinib safety findings were observed. ConclusionsOsimertinib can be co-administered with CYP3A4 inhibitors, but strong CYP3A inducers should be avoided if possible.
Original languageEnglish
Pages (from-to)1156-1169
Number of pages14
JournalBritish Journal of Clinical Pharmacology
Volume84
Issue number6
DOIs
Publication statusPublished - 1 Jun 2018

Keywords

  • clinical pharmacology
  • drug metabolism
  • drug analysis
  • lung cancer
  • drug information
  • oncology
  • pharmacokinetics
  • biomarkers
  • drug interactions
  • CELL LUNG-CANCER
  • SYSTEMIC ANTIMYCOTICS KETOCONAZOLE
  • GROWTH-FACTOR RECEPTOR
  • DRUG-DRUG INTERACTION
  • PHASE-III
  • OPEN-LABEL
  • ACQUIRED-RESISTANCE
  • 1ST-LINE TREATMENT
  • T790M MUTATION
  • EGFR MUTATIONS

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